title: Tobacco-associated pulmonary vascular dysfunction in smokers: role of the ET-1 pathway.
abstract: Pulmonary vascular remodeling and dysfunction associated to tobacco smoking might pave the way for the subsequent development of pulmonary hypertension. Its prognosis is dreadful and its underlying mechanisms are so far largely unknown in humans. To assess the potential role of endothelin-1 and its receptors in smokers' pulmonary artery vasoactive properties. Endothelium-dependent vasodilation to ACh was assessed in pulmonary vascular rings from 34 smokers and compared with that of 10 nonsmokers. The effects of ET-A (BQ 123) or ET-B (BQ 788) blockers and that of an ET-B activator (sarafotoxin) were evaluated. Endothelin-1 was quantitated by ELISA. Expression of its receptors was quantitated by Western blotting. Smokers exhibited an impaired pulmonary endothelium-dependent vasodilation compared with nonsmokers (P < 0.01). In the former group, 8 of 34 subjects exhibited a marked endothelial dysfunction (ED(+)) whereas 26 (ED(-)) (P < 10(-4)) displayed a vasorelaxation to ACh that was comparable to that of nonsmokers. In ED(+) subjects, ET-A was overexpressed (P < 0.05) and inversely correlated (P < 10(-2)) with the response to ACh. Sarafotoxin significantly improved vasodilation in all subjects (P < 10(-2)). In conclusion, tobacco smoking is associated to an impaired pulmonary vasorelaxation at least partly mediated by an ET-1/ET-A-dependent dysfunction.
authors.affiliation: Unité Propre de Recherche de l’Enseignement Supérieur EA, UFR Biomédicale des Saints Pères, Paris, France.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Henno
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Boitiaux
authors.forename: Benoit
authors.initials: B
authors.lastname: Douvry
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cazes
authors.forename: Marilyne
authors.initials: M
authors.lastname: Lévy
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
authors.forename: Christophe
authors.initials: C
authors.lastname: Delclaux
authors.forename: Dominique
authors.initials: D
authors.lastname: Israël-Biet
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology; D015153:Blotting, Western; D002939:Ciprofloxacin / Q000031:analogs & derivatives / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014652:Vascular Diseases / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014665:Vasodilator Agents; C086539:BQ 788; D002939:Ciprofloxacin; D000109:Acetylcholine; C047224:sarafloxacin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)